Drug development: Drug submissions and the harmonized process

In the process of drug development (bringing a drug or biologic to market), obtaining a marketing authorization is the final step. To reach this stage, the data generated during product development must be presented in a drug submission dossier that is specific to each jurisdiction. The drug submission must contain extensive technical data on the quality, safety and efficacy of the product, as well as regional-specific information and documents such as application forms, declarations, patents, labels and leaflets.

When it receives the drug submission, the regulatory authority will review it thoroughly to ensure the evidence for quality, safety and efficacy is satisfactory before it grants a marketing authorization. Only after marketing authorization is issued can the company who owns the product licence commercialize it, and start recouping the money invested in the drug development program.1

International Conference on Harmonisation: Drug submissions and the Common Technical Document

Before the Common Technical Document guideline was developed by the International Conference on Harmonisation (ICH), each regulatory authority required technical data to be presented in a jurisdiction-specific format. For companies who were pursuing global drug development, this involved a great deal of administrative work to reorganize information for each drug submission. The introduction of the CTD provided a more unified approach in presenting regulatory submissions for drugs and biologics. Today, the CTD format has been widely adopted by Canada, the US, the EU, Japan and other jurisdictions.2

The CTD structure covers five modules (the schematic presentation of the CTD structure and hierarchy can be found on the ICH website).2 Module 1 is jurisdiction-specific and thus not a part of the CTD. Modules 2 to 5 are part of the CTD and are intended to be common across jurisdictions.

Module 1 contains information that is specific for each jurisdiction. It includes submission documents such as application forms, the fee form, declarations, proposed labels, the patent(s) and other administrative information. This section is jurisdiction-specific and cannot be harmonized; therefore, it is not a part of the CTD.

Module 2 contains critical overview assessments of the quality, non-clinical and clinical data, together with summaries of non-clinical and clinical data. These summary documents should be cross-referenced to Modules 3, 4 and 5 to facilitate regulatory review.

Module 3 contains information on quality, such as the identity, characteristics, manufacturing methods, control, packaging and stability of the drug substance (DS) and drug product (DP).

Module 4 contains reports of the non-clinical studies that investigated the pharmacological and toxicological properties of the DS and DP.

Module 5 contains clinical study reports and raw data (where applicable) to demonstrate the safety and efficacy of the drug in humans.

Drug submissions: Harmonized, but with specific regional information

The ICH M4 CTD guidance document has significantly streamlined the preparation process for global drug submissions. It offers a harmonized way to present the technical data. Nevertheless, the company pursuing the drug development and compiling these modules needs to be aware that specific regional differences and requirements may exist. For instance:

Health Canada has developed a template for Module 2.3 Quality Overall Summary (QOS) – Chemical Entities (New Drug Submissions/Abbreviated New Drug Submissions). This document outlines the suggested format specific to Canada.3 Also, there are guidance documents for the preparation of QOS for other products (for example, blood products, biotech products)thatinclude product-specific considerations to be addressed in a Canadian New Drug Submission (NDS).4 In your NDS, make sure to include executed production documents, master production documents and information on the medical devices used to deliver the dosage form (if applicable).3

In the US, Module 3 Quality should contain samples of executed batch records, the method validation package and comparability protocols.1,5

In the EU, Module 3 Qualityshould contain:

A process validation scheme for the drug product

Specific forms relating to the prevention of transmissible spongiform encephalopathy (TSE) from animal-derived materials or other infections from materials of human origin

Medical device information if a device is used as part of the drug-delivery system1,5,6

These differences exist because the CTD only provides a harmonized way of organizing the technical information―it does not change the drug submission requirements legislated in each jurisdiction.

For example, the required content of a US New Drug Application (NDA) is outlined in the Food, Drug, and Cosmetic Act and 21 Code of Federal Regulations, Part 314. Using the CTD format, a drug-development company can “map” the specific requirements of an NDA to the relevant section of a CTD to address the US drug submission requirement. Information presented in Modules 2 to 5 can be “recycled” for other jurisdictions as long as regional-specific information is included.

Disclaimer

The information presented in these articles is intended to outline the general processes, principles and concepts of the healthcare product development lifecycle. Since regulatory requirements are ever-changing, it is current only as of the date of publication and not intended to provide detailed instructions for product development. Every healthcare product is unique and therefore so is its associated product development lifecycle. Specific advice should be sought from a qualified healthcare or other appropriate professional.